Alice J Sitch

Sample size calculations for cluster randomised controlled trials with a fixed number of clusters

AbstractBackgroundCluster randomised controlled trials (CRCTs) are frequently used in health service evaluation. Assuming an average cluster size, required sample sizes are readily computed for both binary and continuous outcomes, by estimating a design effect or inflation factor. However, where the number of clusters are fixed in advance, but where it is possible to increase the number of individuals within each cluster, as is frequently the case in health service evaluation, sample size formulae have been less well studied.MethodsWe systematically outline sample size formulae (including required number of randomisation units, detectable difference and power) for CRCTs with a fixed number of clusters, to provide a concise summary for both binary and continuous outcomes. Extensions to the case of unequal cluster sizes are provided.ResultsFor trials with a fixed number of equal sized clusters (k), the trial will be feasible provided the number of clusters is greater than the product of the number of individuals required under individual randomisation (nI ) and the estimated intra-cluster correlation (ρ). So, a simple rule is that the number of clusters (k) will be sufficient provided: Where this is not the case, investigators can determine the maximum available power to detect the pre-specified difference, or the minimum detectable difference under the pre-specified value for power.ConclusionsDesigning a CRCT with a fixed number of clusters might mean that the study will not be feasible, leading to the notion of a minimum detectable difference (or a maximum achievable power), irrespective of how many individuals are included within each cluster.

Widening access to medical education for under-represented socioeconomic groups: population based cross sectional analysis of UK data, 2002-6

Objective To determine whether new programmes developed to widen access to medicine in the United Kingdom have produced more diverse student populations. Design Population based cross sectional analysis. Setting 31 UK universities that offer medical degrees. Participants 34 407 UK medical students admitted to university in 2002-6. Main outcome measures Age, sex, socioeconomic status, and ethnicity of students admitted to traditional courses and newer courses (graduate entry courses (GEC) and foundation) designed to widen access and increase diversity. Results The demographics of students admitted to foundation courses were markedly different from traditional, graduate entry, and pre-medical courses. They were less likely to be white and to define their background as higher managerial and professional. Students on the graduate entry programme were older than students on traditional courses (25.5 v 19.2 years) and more likely to be white (odds ratio 3.74, 95% confidence interval 3.27 to 4.28; P<0.001) than those on traditional courses, but there was no difference in the ratio of men. Students on traditional courses at newer schools were significantly older by an average of 2.53 (2.41 to 2.65; P<0.001) years, more likely to be white (1.55, 1.41 to 1.71; P<0.001), and significantly less likely to have higher managerial and professional backgrounds than those at established schools (0.67, 0.61 to 0.73; P<0.001). There were marked differences in demographics across individual established schools offering both graduate entry and traditional courses. Conclusions The graduate entry programmes do not seem to have led to significant changes to the socioeconomic profile of the UK medical student population. Foundation programmes have increased the proportion of students from under-represented groups but numbers entering these courses are small.

Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism

BACKGROUND. Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess. METHODS. We performed mass spectrometry–based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis. RESULTS. Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients. CONCLUSION. Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism. FUNDING. Medical Research Council UK, Wellcome Trust, European Commission.

Supported self-management for patients with moderate to severe chronic obstructive pulmonary disease (COPD): an evidence synthesis and economic analysis

BACKGROUND Self-management (SM) support for patients with chronic obstructive pulmonary disease (COPD) is variable in its coverage, content, method and timing of delivery. There is insufficient evidence for which SM interventions are the most effective and cost-effective. OBJECTIVES To undertake (1) a systematic review of the evidence for the effectiveness of SM interventions commencing within 6 weeks of hospital discharge for an exacerbation for COPD (review 1); (2) a systematic review of the qualitative evidence about patient satisfaction, acceptance and barriers to SM interventions (review 2); (3) a systematic review of the cost-effectiveness of SM support interventions within 6 weeks of hospital discharge for an exacerbation of COPD (review 3); (4) a cost-effectiveness analysis and economic model of post-exacerbation SM support compared with usual care (UC) (economic model); and (5) a wider systematic review of the evidence of the effectiveness of SM support, including interventions (such as pulmonary rehabilitation) in which there are significant components of SM, to identify which components are the most important in reducing exacerbations, hospital admissions/readmissions and improving quality of life (review 4). METHODS The following electronic databases were searched from inception to May 2012: MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Science Citation Index [Institute of Scientific Information (ISI)]. Subject-specific databases were also searched: PEDro physiotherapy evidence database, PsycINFO and the Cochrane Airways Group Register of Trials. Ongoing studies were sourced through the metaRegister of Current Controlled Trials, International Standard Randomised Controlled Trial Number database, World Health Organization International Clinical Trials Registry Platform Portal and ClinicalTrials.gov. Specialist abstract and conference proceedings were sourced through ISIs Conference Proceedings Citation Index and British Librarys Electronic Table of Contents (Zetoc). Hand-searching through European Respiratory Society, the American Thoracic Society and British Thoracic Society conference proceedings from 2010 to 2012 was also undertaken, and selected websites were also examined. Title, abstracts and full texts of potentially relevant studies were scanned by two independent reviewers. Primary studies were included if ≈90% of the population had COPD, the majority were of at least moderate severity and reported on any intervention that included a SM component or package. Accepted study designs and outcomes differed between the reviews. Risk of bias for randomised controlled trials (RCTs) was assessed using the Cochrane tool. Random-effects meta-analysis was used to combine studies where appropriate. A Markov model, taking a 30-year time horizon, compared a SM intervention immediately following a hospital admission for an acute exacerbation with UC. Incremental costs and quality-adjusted life-years were calculated, with sensitivity analyses. RESULTS From 13,355 abstracts, 10 RCTs were included for review 1, one study each for reviews 2 and 3, and 174 RCTs for review 4. Available studies were heterogeneous and many were of poor quality. Meta-analysis identified no evidence of benefit of post-discharge SM support on admissions [hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.52 to 1.17], mortality (HR 1.07, 95% CI 0.74 to 1.54) and most other health outcomes. A modest improvement in health-related quality of life (HRQoL) was identified but this was possibly biased due to high loss to follow-up. The economic model was speculative due to uncertainty in impact on readmissions. Compared with UC, post-discharge SM support (delivered within 6 weeks of discharge) was more costly and resulted in better outcomes (£683 cost difference and 0.0831 QALY gain). Studies assessing the effect of individual components were few but only exercise significantly improved HRQoL (3-month St Georges Respiratory Questionnaire 4.87, 95% CI 3.96 to 5.79). Multicomponent interventions produced an improved HRQoL compared with UC (mean difference 6.50, 95% CI 3.62 to 9.39, at 3 months). Results were consistent with a potential reduction in admissions. Interventions with more enhanced care from health-care professionals improved HRQoL and reduced admissions at 1-year follow-up. Interventions that included supervised or unsupervised structured exercise resulted in significant and clinically important improvements in HRQoL up to 6 months. LIMITATIONS This review was based on a comprehensive search strategy that should have identified most of the relevant studies. The main limitations result from the heterogeneity of studies available and widespread problems with their design and reporting. CONCLUSIONS There was little evidence of benefit of providing SM support to patients shortly after discharge from hospital, although effects observed were consistent with possible improvement in HRQoL and reduction in hospital admissions. It was not easy to tease out the most effective components of SM support packages, although interventions containing exercise seemed the most effective. Future work should include qualitative studies to explore barriers and facilitators to SM post exacerbation and novel approaches to affect behaviour change, tailored to the individual and their circumstances. Any new trials should be properly designed and conducted, with special attention to reducing loss to follow-up. Individual participant data meta-analysis may help to identify the most effective components of SM interventions. STUDY REGISTRATION This study is registered as PROSPERO CRD42011001588. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Early Warning Scores Generated in Developed Healthcare Settings Are Not Sufficient at Predicting Early Mortality in Blantyre, Malawi: A Prospective Cohort Study

Aim Early warning scores (EWS) are widely used in well-resourced healthcare settings to identify patients at risk of mortality. The Modified Early Warning Score (MEWS) is a well-known EWS used comprehensively in the United Kingdom. The HOTEL score (Hypotension, Oxygen saturation, Temperature, ECG abnormality, Loss of independence) was developed and tested in a European cohort; however, its validity is unknown in resource limited settings. This study compared the performance of both scores and suggested modifications to enhance accuracy. Methods A prospective cohort study of adults (≥18 yrs) admitted to medical wards at a Malawian hospital. Primary outcome was mortality within three days. Performance of MEWS and HOTEL were assessed using ROC analysis. Logistic regression analysis identified important predictors of mortality and from this a new score was defined. Results Three-hundred-and-two patients were included. Fifty-one (16.9%) died within three days of admission. With a cut-point ≥2, the HOTEL score had sensitivity 70.6% (95% CI: 56.2 to 82.5) and specificity 59.4% (95% CI: 53.0 to 65.5), and was superior to MEWS (cut-point ≥5); sensitivity: 58.8% (95% CI: 44.2 to 72.4), specificity: 56.2% (95% CI: 49.8 to 62.4). The new score, dubbed TOTAL (Tachypnoea, Oxygen saturation, Temperature, Alert, Loss of independence), showed slight improvement with a cut-point ≥2; sensitivity 76.5% (95% CI: 62.5 to 87.2) and specificity 67.3% (95% CI: 61.1 to 73.1). Conclusion Using an EWS generated in developed healthcare systems in resource limited settings results in loss of sensitivity and specificity. A score based on predictors of mortality specific to the Malawian population showed enhanced accuracy but not enough to warrant clinical use. Despite an assumption of common physiological responses, disease and population differences seem to strongly determine the performance of EWS. Local validation and impact assessment of these scores should precede their adoption in resource limited settings.

Earlier intervention for acute kidney injury: evaluation of an outreach service and a long-term follow-up

BACKGROUND There have been few studies of earlier systematic intervention to reduce the impact of acute kidney injury (AKI). In 2009, we piloted an AKI outreach service with a before and after study, and we report on the study and its longer-term follow-up. METHODS AKI patients were identified using a laboratory delta check for creatinine of 75%. In the 4-week before phase patients received standard care. In a consecutive 7-week after phase an outreach team of nephrology doctors and nurses reviewed all alerts twice daily, 5 days a week. The primary clinical team caring for the patient was called to be given advice on AKI care. RESULTS There were 157 and 251 patients in the before and after groups, respectively, who were comparable in their characteristics. The mean age was 70 years in both groups and ∼ 80% of each group were admitted to the hospital. In the after group, the Outreach telephone call was successful in 88%, at a median of 14 h. Substantial numbers of recommendations were made, largely related to fluid balance, investigations and medication use. Survival showed an immediate non-significant improvement in the after group, but converged at about 4 years. CONCLUSION Outreach shows potential to improve outcomes in AKI. In order to achieve this it seems likely that at least a five-day per week service will be needed to assist good renal and general medical care for this vulnerable group.

Targeted case finding for chronic obstructive pulmonary disease versus routine practice in primary care (TargetCOPD): a cluster-randomised controlled trial

BACKGROUND Many individuals with chronic obstructive pulmonary disease (COPD) remain undiagnosed worldwide. Health-care organisations are implementing case-finding programmes without good evidence of which are the most effective and cost-effective approaches. We assessed the effectiveness and cost-effectiveness of two alternative approaches to targeted case finding for COPD compared with routine practice. METHODS In this cluster-randomised controlled trial, participating general practices in the West Midlands, UK, were randomly assigned (1:1), via a computer-generated block randomisation sequence, to either a targeted case-finding group or a routine care group. Eligible patients were ever-smokers aged 40-79 years without a previously recorded diagnosis of COPD. Patients in the targeted case-finding group were further randomly assigned (1:1) via their household to receive either a screening questionnaire at the general practitioner (GP) consultation (opportunistic) or a screening questionnaire at the GP consultation plus a mailed questionnaire (active). Respondents reporting relevant respiratory symptoms were invited for post-bronchodilator spirometry. Patients, clinicians, and investigators were not masked to allocation, but group allocation was concealed from the researchers who performed the spirometry assessments. Primary outcomes were the percentage of the eligible population diagnosed with COPD within 1 year (defined as post-bronchodilator forced expiratory volume in 1 s [FEV1] to forced vital capacity [FVC] ratio <0·7 in patients with symptoms or a new diagnosis on their GP record) and cost per new COPD diagnosis. Multiple logistic and Poisson regression were used to estimate effect sizes. Costs were obtained from the trial. This trial is registered with ISRCTN, number ISRCTN14930255. FINDINGS From Aug 10, 2012, to June 22, 2014, 74 818 eligible patients from 54 diverse general practices were randomly assigned and completed the trial. At 1 year, 1278 (4%) cases of COPD were newly detected in 32 789 eligible patients in the targeted case-finding group compared with 337 (1%) cases in 42 029 patients in the routine care group (adjusted odds ratio [OR] 7·45 [95% CI 4·80-11·55], p<0·0001). The percentage of newly detected COPD cases was higher in the active case-finding group (822 [5%] of 15 378) than in the opportunistic case-finding group (370 [2%] of 15 387; adjusted OR 2·34 [2·06-2·66], p<0·0001; adjusted risk difference 2·9 per 100 patients [95% CI 2·3-3·6], p<0·0001). Active case finding was more cost-effective than opportunistic case finding (£333 vs £376 per case detected, respectively). INTERPRETATION In this well established primary care system, routine practice identified few new cases of COPD. An active targeted approach to case finding including mailed screening questionnaires before spirometry is a cost-effective way to identify undiagnosed patients and has the potential to improve their health. FUNDING National Institute for Health Research.

Cost-effectiveness of a community-based physical activity programme for adults (Be Active) in the UK: an economic analysis within a natural experiment

Objective To determine the cost-effectiveness of a physical activity programme (Be Active) aimed at city-dwelling adults living in Birmingham, UK. Methods Very little is known about the cost-effectiveness of public health programmes to improve city-wide physical activity rates. This paper presents a cost-effectiveness analysis that compares a physical activity intervention (Be Active) with no intervention (usual care) using an economic model to quantify the reduction in disease risk over a lifetime. Metabolic equivalent minutes achieved per week, quality-adjusted life years (QALYs) gained and healthcare costs were all included as the main outcome measures in the model. A cost-benefit analysis was also conducted using ‘willingness-to-pay’ as a measure of value. Results Under base-case assumptions—that is, assuming that the benefits of increased physical activity are sustained over 5 years, participation in the Be Active programme increased quality-adjusted life expectancy by 0.06 years, at an expected discounted cost of £3552, and thus the cost-effectiveness of Be Active is £400 per QALY. When the start-up costs of the programme are removed from the economic model, the cost-effectiveness is further improved to £16 per QALY. The societal value placed on the Be Active programme was greater than the operation cost therefore the Be Active physical activity intervention results in a net benefit to society. Conclusions Participation in Be Active appeared to be cost-effective and cost-beneficial. These results support the use of Be Active as part of a public health programme to improve physical activity levels within the Birmingham-wide population.

Self-management of health care behaviors for COPD: a systematic review and meta-analysis

Purpose This systematic review aimed to identify the most effective components of interventions to facilitate self-management of health care behaviors for patients with COPD. PROSPERO registration number CRD42011001588. Methods We used standard review methods with a systematic search to May 2012 for randomized controlled trials of self-management interventions reporting hospital admissions or health-related quality of life (HRQoL). Mean differences (MD), hazard ratios, and 95% confidence intervals (CIs) were calculated and pooled using random-effects meta-analyses. Effects among different subgroups of interventions were explored including single/multiple components and multicomponent interventions with/without exercise. Results One hundred and seventy-three randomized controlled trials were identified. Self-management interventions had a minimal effect on hospital admission rates. Multicomponent interventions improved HRQoL (studies with follow-up >6 months St George’s Respiratory Questionnaire (MD 2.40, 95% CI 0.75–4.04, I2 57.9). Exercise was an effective individual component (St George’s Respiratory Questionnaire at 3 months MD 4.87, 95% CI 3.96–5.79, I2 0%). Conclusion While many self-management interventions increased HRQoL, little effect was seen on hospital admissions. More trials should report admissions and follow-up participants beyond the end of the intervention.

Differences in axial segment reorientation during standing turns predict multiple falls in older adults

BACKGROUND The assessment of standing turning performance is proposed to predict fall risk in older adults. This study investigated differences in segmental coordination during a 360° standing turn task between older community-dwelling fallers and non-fallers. METHODS Thirty-five older adults age mean (SD) of 71 (5.4) years performed 360° standing turns. Head, trunk and pelvis position relative to the laboratory and each other were recorded using a Vicon motion analysis system. Fall incidence was monitored by monthly questionnaire over the following 12 months and used to identify non-faller, single faller and multiple faller groups. RESULTS Multiple fallers were found to have significantly different values, when compared to non-fallers, for pelvis onset (p=0.002); mean angular separation in the transverse plane between the head and trunk (p=0.018); peak angular separation in the transverse plane between the trunk and pelvis (p=0.013); and mean angular separation between the trunk and pelvis (p<0.001). CONCLUSIONS Older adults who subsequently experience multiple falls show a simplified turning pattern to assist in balance control. This may be a predictor for those at increased risk of falling.